This invention relates to biologically active materials and, in particular, to materials which comprise a biodegradable polymer linked to a biologically active agent. The invention is concerned with materials known as polymer-drug conjugates which typically contain a therapeutic agent for instance, a bioactive cytotoxic drug, linked to a polymer back-bone. The linkage between the polymer and the drug is typically by covalent bonding. However, the invention is applicable to other polymer conjugates including those where the biologically active agent is an imaging agent, such as tyrosinamide, a diagnostic agent, or a targeting agent such as biotin.
Reference will be made hereinbelow to polymer-drug conjugates in which the drugs are anticancer agents. However, the present invention has application in connection with other drugs and/or bioactive agents.
In designing a polymer-drug conjugate, the aim is to deliver a drug effectively to a therapeutic site such as a tumour. It is known, for instance, that polymer-drugs given intravenously can accumulate selectively in solid tumour tissue by the EPR effect.
The most commonly used anticancer agents are low molecular weight compounds which readily gain access to cells by rapid passage across the cell membrane. After intravenous (IV) administration, a large percentage of the injected dose leaves the circulation within a few minutes, resulting in a ubiquitous body distribution of drug and little selective concentration in tumour tissue. By creating a macromolecular polymer-anticancer drug conjugate, there is provided an opportunity to improve tumour specific targeting, to minimise drug entry into sites of toxicity, to control precisely the rate of drug liberation at the target site (giving opportunities for long-term controlled release) and to deliver the active principal intracellularly, thereby providing a means to overcome p-glycoprotein related multidrug resistance.
Numerous polymers have been proposed for synthesis of polymer-drug conjugates including polyaminoacids, polysaccharides such as dextran, and synthetic polymers such as N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer. However, these polymers have limitations. For example, a dextran-doxorubicin conjugate has been tested clinically and been found to be much more toxic than the parent drug. Furthermore the HPMA copolymers which have been clinically tested have the disadvantage of being non-biodegradable in the main chain.
WO-A-98/56424 discloses a polymer-drug conjugate in which the polymer is the polysaccharide dextrin. Such a polymer-drug conjugate may be prepared in various ways. One method involves succinoylating dextrin and reacting the succinoylated dextrin with the drug or a reactive derivative thereof.
WO-A-98/56424 includes an example in which the extent of succinoylation of dextrin varies from 2.26 to 6.64 Mol %. In a further example the drug doxorubicin is conjugated to succinoylated dextrins in which the extent of succinoylation varies from 0.5 to 14.9 Mol %.
WO-A-98/56424 also includes examples showing the rate of degradation of dextrin both in the absence and in the presence of appropriate enzymes and also in rat plasma.
For at least certain applications the rate of degradation of dextrin in a dextrin-drug conjugate is an important consideration. For instance, it may be desirable to have a relatively slow rate of degradation in some applications while in other applications a faster rate of degradation is either acceptable or indeed even preferred.
It has now been surprisingly discovered that the rate of dextrin degradation is highly dependent on the degree of dextrin backbone substitution. As a result, it is possible to tailor the dextrin by appropriate substitution of its backbone in order to achieve a desired rate of degradation.
According to a first aspect of the invention there is provided a polymer drug conjugate comprising:
i) at least one anti-cancer drug; and
ii) a dextrin polymer
characterised in that said dextrin polymer is modified by the addition of pendent groups so that the stability of the polymer drug conjugate is enhanced.
The term xe2x80x9cdextrinxe2x80x9d means a glucose polymer which is produced by the hydrolysis of starch and which consists of glucose units linked together by means mainly of alpha-1,4 linkages. Typically dextrins are produced by the hydrolysis of starch obtained from various natural products such as wheat, rice, maize and tapioca. In addition to alpha-1,4 linkages, there may be a proportion of alpha-1,6 linkages in a particular dextrin, the amount depending on the starch starting material. Since the rate of biodegradability of alpha-1,6 linkages is typically less than that for alpha-1,4 linkages, for many applications it is preferred that the percentage of alpha-1,6 linkages is less than 10% and more preferably less than 5%.
Any dextrin is a mixture of polyglucose molecules of different chain lengths. As a result, no single number can adequately characterise the molecular weight of such a polymer. Accordingly various averages are used, the most common being the weight average molecular weight (Mw) and the number average molecular weight (Mn). Mw is particularly sensitive to changes in the high molecular weight content of a polymer whilst Mn is largely influenced by changes in the low molecular weight of the polymer.
It is preferred that the Mw of the dextrin is in the range from 1,000 to 200,000, more preferably from 2,000 to 55,000.
The term xe2x80x98degree of polymerisationxe2x80x99 (DP) can also be used in connection with polymer mixtures. For a single polymer molecule, DP means the number of polymer units. For a mixture of molecules of different DP""s, weight average DP and number average DP correspond to Mw and Mn. In addition DP can also be used to characterise a polymer by referring to the polymer mixture having a certain percentage of polymers of DP greater than a particular number or less than a particular number.
It is preferred that, in the dextrin-drug conjugate of the present invention, the dextrin contains more than 15% of polymers of DP greater than 12 and, more preferably, more than 50% of polymers of DP greater than 12.
Modifications to dextrin may be negatively charged groups, neutral groups or positively charged groups, (eg quaternary ammonium groups).
In a further preferred embodiment of the invention said dextrin modification is succinoylation.
In a yet further preferred embodiment of the invention said dextrin succinoylation is greater than 20 mol %. Preferably said dextrin succinoylation is at least 30 mol %. More prefereably still said succinoylation is from 30% to 40%.
More preferably still said succinoylation is 30 mol %; 31 mol %; 32 mol %; 33 mol %; 34 mol %; 35 mol %; 36 mol %; 37 mol %; 38 mol %; 39 mol %; 40 mol %. Ideally said succinoylation is 34 mol %.
In a yet further preferred embodiment of the invention said succinoylated dextrin comprises an anti-cancer agent selected from: cyclophosphamide; melphalan; carmusline; methotrexate, 5-fluorouracil; cytarabine; mercaptopurine; anthracyclines; daunorubicin; doxorubicin; epirubicin; vinca alkaloids; vinblastin; vincristine; dactinomycin; mitomycin C; taxol; L-asparaginase; G-CSF; cisplatin; carboplatin.
More preferably still said anti-cancer agent is doxorubicin.
According to a further aspect of the invention there is provided a pharmaceutical composition comprising a polymer drug conjugate according to any previous aspect or embodiment of the invention.
In a preferred embodiment of the invention said composition comprises a diluent, carrier or excipient.
In a further preferred embodiment of the invention said polymer drug conjugate is for use in the manufacture of a medicament for the treatment of cancer.
According to a further aspect of the invention there is provided a method to treat an animal, ideally a human being, suffering from cancer by administration of the polymer drug conjugate according to the invention.
It has been found that, in the case of substitution of the dextrin backbone by succinoylation, relatively rapid degradation takes place at a degree of succinoylation of up to about 15%. By contrast a degree of succinoylation above 30% very markedly reduces the rate of degradation.
The present invention provides a dextrin-drug conjugate in which the degree of substitution of the dextrin chain is greater than 15%, more preferably greater than 20% and most preferably greater than 30%.
The drug of the dextrin-drug conjugate may be loaded on the polymer via a linking group, such as succinoyl, in which case it may be attached to some or all of the linking groups. Alternatively the drug may be directly loaded onto the dextrin backbone in which case the drug itself acts as the substituting group. As a further possibility the drug may be loaded partly via a substituting group and partly directly onto the dextrin backbone.